Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain

Department of Psychiatry, Columbia University, New York, New York, United States
Human Molecular Genetics (Impact Factor: 6.39). 06/2007; 16(10):1133-42. DOI: 10.1093/hmg/ddm054
Source: PubMed


Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Here, we provide evidence supporting the hypothesis that somatic increases of mutation length play a role in the progressive nature and cell-selective aspects of HD pathogenesis. Results from micro-dissected tissue and individual laser-dissected cells obtained from human HD cases and knock-in HD mice indicate that the CAG repeat is unstable in all cell types tested although neurons tend to have longer mutation length gains than glia. Mutation length gains occur early in the disease process and continue to accumulate as the disease progresses. In keeping with observed patterns of cell loss, neuronal mutation length gains tend to be more prominent in the striatum than in the cortex of low-grade human HD cases, less so in more advanced cases. Interestingly, neuronal sub-populations of HD mice appear to have different propensities for mutation length gains; in particular, smaller mutation length gains occur in nitric oxide synthase-positive striatal interneurons (a relatively spared cell type in HD) compared with the pan-striatal neuronal population. More generally, the data demonstrate that neuronal changes in HD repeat length can be at least as great, if not greater, than those observed in the germline. The fact that significant CAG repeat length gains occur in non-replicating cells also argues that processes such as inappropriate mismatch repair rather than DNA replication are involved in generating mutation instability in HD brain tissue.

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    • "[24] [25] [26] [27]). Expansions have been observed in non-dividing cells in affected humans including neurons of patients with Huntington disease (HD) [28] [29], Dentatorubral–pallidoluysian atrophy (DRPLA) [30] and Friedreich ataxia (FRDA) [31]. Expansions are also seen in the oocytes of women with myotonic dystrophy type 1 (DM1) [32] [33] and a maternal age effect is seen on the transmission of expanded alleles in DM1, fragile X syndrome (FXS) and FRDA [13] [34] [35]. "
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    • "To assess RTEL1 and Fbh1 activity toward expansions , we combined small interfering RNA (siRNA) treatment with a previously described TNR expansion assay (Experimental Procedures; Figure S1). A human astrocytic cell line, SVG-A, was used because these cells support expansions in culture (Debacker et al., 2012; Gannon et al., 2012) and because in vivo expansions occur in glia (Shelbourne et al., 2007). Knockdown of Fbh1 in SVG-A cells produced virtually no change (<8%) in expansion frequencies (Figure 1A). "
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    • "The threshold CAG repeat length that causes HD is ∼36, and there is an approximate correlation between the length of the CAG tract and the age of onset of the disease (25–27). Confounding this relationship is instability of repeat length, which occurs both in humans (28–32) and in mouse models of HD (33–37). In fact, super-long CAG expansions up to 1000 have been found in neurons from the brains of patients with adult-onset HD (31,35). "
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